1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-κB pathway

Deb DK, Chen Y, Zhang Z, Zhang Y, Szeto FL, Wong KE, Kong J, Li YC. 1,25-Dihydroxyvitamin D-3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-kappa B pathway. Am J Physiol Renal Physiol 296: F1212-F1218, 2009. First published February 4, 2009; doi:10.1152/ajprenal.00002.2009.-The renin-angiotensin system (RAS) is a major mediator of renal injury in diabetic nephropathy. Our previous studies demonstrated that 1,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] plays a renoprotective role by suppressing the RAS, with renin and angiotensinogen (AGT) as the main targets. The mechanism whereby 1,25(OH)(2)D-3 transcriptionally suppresses renin gene expression has been elucidated; however, how vitamin D regulates AGT remains unknown. Exposure of mesangial cells or podocytes to high glucose (HG; 30 mM) markedly stimulated AGT expression. In mesangial cells, the stimulation was inhibited by 1,25(OH)(2)D-3 (20 nM) or NF-kappa B inhibitor BAY 11-7082, suggesting the involvement of NF-kappa B in HG-induced AGT expression and the interaction between 1,25(OH)(2)D-3 and NF-kappa B in the regulation. Plasmid pNF-kappa B-Luc luciferase reporter assays showed that 1,25(OH)(2)D-3 blocked HG-induced NF-kappa B activity. EMSA and ChIP assays demonstrated increased p65/p50 binding to a NF-kappa B binding site at -1734 in the AGT gene promoter upon high glucose stimulation, and the binding was disrupted by 1,25(OH)(2)D-3 treatment. Overexpression of p65/p50 overcame 1,25(OH)(2)D-3 suppression, and mutation of this NF-kappa B binding site blunted 1,25(OH)(2)D-3 suppression of the promoter activity. In mice lacking the vitamin D receptor, AGT mRNA expression in the kidney was markedly increased compared with wild-type mice, and AGT induction in diabetic mice was suppressed by treatment with a vitamin D analog. These data indicate that 1,25(OH)(2)D-3 suppresses hyperglycemia-induced AGT expression by blocking NF-kappa B-mediated pathway.